A Phase II Randomized Trial of Amphotericin B Alone or Combined with Fluconazole in the Treatment of HIV-Associated Cryptococcal Meningitis
A Phase II Randomized Trial of Amphotericin B Alone or Combined with Fluconazole in the Treatment of HIV-Associated Cryptococcal Meningitis
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DOI：
10.1086/599112
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发表时间：
2009-06-15
影响因子：
11.8
通讯作者：
Filler, Scott G.
中科院分区：
文献类型：
--
作者：
Pappas, Peter G.;Chetchotisakd, Ploenchan;Filler, Scott G.
背景隐球菌病是人类免疫缺陷病毒（HIV）感染患者的一种危及生命的感染。治疗中枢神经系统隐球菌病的治疗选择是有限的，特别是在资源有限的情况下。我们进行了一项随机、开放标签、在泰国和美国进行的一项II期试验，比较了静脉注射0.7 mg/kg阿替霉素B脱氧胆酸盐（AmB）的安全性和有效性（标准治疗）与AmB 0.7 mg/kg+氟康唑400 mg（低剂量组合）或AmB 0.7 mg/kg+氟康唑800 mg（高剂量组合）每天给药14天，然后以随机剂量（每天400或800 mg）单独使用氟康唑56天。主要安全性终点是严重或危及生命的治疗相关毒性的数量;主要疗效终点是治疗14天后生存率、神经系统稳定性和脑脊液培养阴性结果的复合终点。共入组143例患者。3组间治疗相关毒性无差异。毒性是可预测的，最常与AmB相关，包括电解质异常、贫血、肾毒性和输注相关事件。在第14天，标准治疗组、低剂量联合治疗组和高剂量联合治疗组分别有41%、27%和54%的患者表现出成功结局。在第42天和第70天，联合治疗组的结果有改善的趋势。AmB加氟康唑以800 mg的剂量给药14天，然后氟康唑以800 mg的剂量每天给药56天，在HIV阳性的中枢神经系统隐球菌病患者中耐受性良好且有效。这些结果具有重要的治疗意义，应在随机III期临床试验中进行验证。该临床试验在国家医学图书馆注册处（http：//www.example.com）注册，注册号为NCT 00145249。www.clinicaltrials.gov
Background. Cryptococcosis is a life-threatening infection among patients with human immunodeficientcy virus (HIV) infection. Therapeutic options for the treatment of central nervous system cryptococcosis are limited, especially in resource-limited settings.Methods. We conducted a randomized, open-label, phase II trial in Thailand and the United States that compared the safety and efficacy of intravenous amphotericin B deoxycholate (AmB) 0.7 mg/kg (the standard therapy) with that of AmB 0.7 mg/kg plus fluconazole 400 mg (the low-dosage combination) or AmB 0.7 mg/kg plus fluconazole 800 mg (the high-dosage combination) administered daily for 14 days, followed by fluconazole alone at the randomized dosage (400 or 800 mg per day) for 56 days. The primary safety end point was the number of severe or life-threatening treatment-related toxicities; the primary efficacy end point was a composite of survival, neurologic stability, and negative cerebrospinal fluid culture results after 14 days of therapy.Results. A total of 143 patients were enrolled. There were no differences in treatment-related toxicities among the 3 arms. Toxicity was predictable and was most often related to AmB, and it included electrolyte abnormalities, anemia, nephrotoxicity, and infusion-related events. At day 14, 41%, 27%, and 54% of patients in the standard therapy, low-dosage combination, and high-dosage combination therapy arms, respectively, demonstrated successful outcomes. A trend towards better outcomes in the combination therapy arms was seen at days 42 and 70.Conclusions. AmB plus fluconazole administered at a dosage of 800 mg for 14 days, followed by fluconazole administered at a dosage of 800 mg daily for 56 days, is well-tolerated and efficacious among HIV-positive patients with central nervous system cryptococcosis. These results have significant treatment implications and should be validated in a randomized phase III trial.Clinical trials registration. This clinical trial is registered in the National Library of Medicine's registry (http://www.clinicaltrials.gov) under the registration number NCT00145249.